The cellular and molecular responses of the lung to oxidative stress involve increased expression of antioxidant enzymes and stress-response genes, including the stress-inducible gene heme oxygenase-1 (HO-1). Heme oxygenase (HO) catalyzes the first and rate limiting step in the degradation of heme to yield equimolar quantities of biliverdin IXa, carbon monoxide (CO), and iron. Our laboratory and others have demonstrated that induction of HO-1 provides cytoprotection both in vivo and in vitro against oxidative stress including but not limited to hyperoxia, ischemia-reperfusion, hydrogen peroxide, and endotoxin. The mechanism(s) by which HO-1 provides cytoprotection against oxidant-induced tissue injury is poorly understood. Our recent studies highlight the formal possibility that the gaseous molecule CO, a catalytic by-product of HO catalysis, can mediate the protective effects against oxidant-induced lung injury. Furthermore, we have demonstrated that CO mediates the cytoprotection via the MKK3/p38 mitogen activated protein kinase (MAPK) signaling pathway. Our recent data supports the hypothesis that p38B, a specific isoform of p38 MAPK, mediates COinduced cytoprotection. We further hypothesize that CO mediates cytoprotection by activation of the stress response gene HSP70 via the p38B pathway. We will test this hypothesis by addressing the following aims: 1) To determine whether CO-induced p38B mediates cytoprotection against hyperoxia 2) To determine the function of CO-induced HSP70 activation in vitro and in vivo 3) To determine the mechanism by which CO-induced p38B activation confers cytoprotection against hyperoxia-induced cell death 4) To identify key intermediary signaling molecules mediating CO-induced cytoprotection against hyperoxia